The present invention relates to antibacterial compounds which are 7-acylamino-3-(imino)methyl cephalosporins.
Particularly the present invention provides a compound of formula 
wherein
R1 denotes hydrogen or an ester moiety,
R2 denotes a group of formula 
xe2x80x83wherein
Y denotes hydrogen, alkyl, alkenyl, acyl, carbamoyl or aryl
R4 denotes hydrogen, alkyl, alkenyl, cycloalkyl, aryl, acyl or heterocyclyl
R5 denotes hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, or a group of formula 
xe2x80x83wherein
R7 denotes alkyl or aryl
R8 denotes hydrogen, cycloalkyl or alkyl
R9 denotes hydrogen or alkyl
R10 denotes hydrogen, alkyl, hydroxy, amino, phenyl, alkenyl, cycloalkyl,aryl, heterocyclyl or a group of formula
xe2x80x94Nxe2x95x90CH-Phe
xe2x80x83wherein Phe denotes aryl
R9 and R10 together with the nitrogen atom denote heterocyclyl,
Z denotes oxygen, sulphur or Nxe2x80x94R13, wherein
R13 denotes hydrogen, alkyl or cycloalkyl
R11 denotes hydrogen, alkyl, aryl, cycloalkyl or heterocyclyl, or
R4 and R5 together with the nitrogen atom denote heterocyclyl,
R6 denotes heterocyclyl, and
Ac denotes
(i) a group 
(ii) a group of formula 
xe2x80x83wherein
B denotes N or CH
Z1 denotes aryl, cycloalkyl, 1,4-cyclohexadienyl or heterocyclyl
Z2 denotes hydrogen, alkyl or xe2x80x94CH2COOZ5, wherein
Z5 denotes hydrogen, alkyl or cycloalkyl
Z3 denotes hydrogen or alkyl
Z4 denotes hydrogen or an organic radical
D denotes oxygen or CH2.
A subgroup of the invention comprises any of the individual groups of significances mentioned therein.
R1 may be hydrogen or an ester moiety. An ester moiety includes alkyl, preferably C1-6alkyl; arylalkyl, for example benzyl, alkoxybenzyl, such as 4-methoxybenzyl; indanyl, phthalidyl, alkoxymethyl, e.g. methoxymethyl; (C1-6)alkanoyloxy(C1-6)alkyl, (C1-6)alkoxycarbonyl-oxy(C1-6)alkyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen4-yl)methyl and ester moieties which form with the COOxe2x80x94 group a physiologically hydrolysable and acceptable ester, e.g. such known to be hydrolysable ester groups in the field of cephalosporins. A compound of formula I may thus be in the form of an physiologically-hydrolysable and -acceptable ester. By physiologically-hydrolysable and -acceptable esters as used herein is meant an ester in which the COOxe2x80x94 group is esterified and which is hydrolysable under physiological conditions to yield an acid which is itself physilogically tolerable at dosages to be administered. The term is thus to be understood as defining regular pro-drug forms. An ester moiety may be preferably a group which is easily hydrolysable under physiological conditions. Such esters may be administered preferably orally. Parenteral administration may be indicated if the ester per se is an active compound or, if hydrolysis occurs in the blood.
Y may be preferably hydrogen, unsubstituted alkyl or alkyl substituted by e.g. hydroxy or, preferably the residue of a carboxylic acid. The residue of a carboxylic acid includes the residue of a carboxylic acid in free form or in salt form, of a carboxylic acid ester and of a carboxylic acid amide. The carboxylic acid is, for example, a C1-7 carboxylic acid, preferably a C1-5 aliphatic carboxylic acid, an alkyl part thereof including lower alkyl. The alkoxy group of a carboxylic acid ester includes C1-6, preferably C1-4alkoxy. Alkyl is preferably lower alkyl. The alkyl group is preferably unsubstituted or substituted by carboxylic acid residues.
R4 may be preferably hydrogen or alkyl, for example lower alkyl.
R5 may be preferably hydrogen; unsubstituted alkyl; alkyl substituted for example by oxo, alkyl or halogenated alkyl; amino; one or several fold substituted heterocyclyl; or a group of formulae IId, IIe, IIf. Heterocyclyl includes unsaturated or saturated heterocyclyl having, e.g. 5 or 6 ring members and, for example, 1 to 3 hetero atoms, such as N, O, S, preferably N, or condensed heterocyclyl, such as benzothiazolyl.
R4 and R5 together with the nitrogen atom may be heterocyclyl, having preferably 5 or 6 ring members and having preferably 1 to 3 heteroatoms, for example N atoms; which may be unsubstituted heterocyclyl; or one or several fold substituted heterocyclyl, for example by oxo, amino, alkyl.
R6 may be saturated or unsaturated heterocyclyl; having preferably 5 or 6 ring members and having for example 1 or 2 nitrogen hetero atoms; for example unsubstituted heterocylclyl; or one or several fold substituted heterocyclyl, for example by amino, alkyl or thiono.
R7 may be preferably alkyl.
R8 may be preferably alkyl or cycloalkyl.
R9 may be preferably hydrogen or lower alkyl.
R13 may be preferably alkyl.
R10 may be preferably hydrogen; aryl; alkenyl; cycloalkyl; unsubstituted alkyl; substituted alkyl, for example by hydroxy, halogen, heterocyclyl, such as pyridyl, amino, for example N(alkyl)2 or N+(alkyl)3; or a group
xe2x80x94Nxe2x95x90/CH-Ar
wherein Ar denotes heterocyclyl; unsubstituted aryl; or substituted aryl, for example by hydroxy or alkoxy; preferably aryl which may be preferably phenyl.
R9 and R10 together with the nitrogen atom may be heterocyclyl having preferably 5 or 6 ring members and 1 to 3 hetero atoms such as N, S, O, for example N, O; preferably saturated heterocyclyl. Heterocyclyl includes unsubstituted heterocyclyl, or substituted heterocyclyl, for example by acyl, formyl, alkyl, for example lower alkyl. Examples include pyrrolidine, morpholine, piperazine, preferably piperazine.
R11 may be preferably hydrogen; unsubstituted alkyl; substituted alkyl, for example by aminoalkyl, diaminoalkyl, triaminoalkyl; aryl, such as dihydroxyphenyl; cycloalkyl; or unsubstituted heterocyclyl; or substituted heterocyclyl, for example by alkyl, thiono heterocyclyl; heterocyclyl having preferably 5 or 6 ring members and 1 to 3 hetero, preferably N atoms.
If not otherwise stated therein any carbon containing group may contain up to 20 carbon atoms, e.g. alkyl includes C1-20, e.g. C1-8 alkyl. Lower alkyl includes e.g. C1-4alkyl, preferably C1-2alkyl. Alkenyl includes C2-20, e.g. C2-8 alkenyl. Lower alkenyl includes e.g. C3-5alkenyl, preferably C3alkyl. Cycloalkyl includes, for example, C3-6Cycloalkyl, particularly C3, C5 or C6cycloalkyl. Alkyl, alkenyl and cycloalkyl include unsubstituted alkyl, alkenyl and cycloalkyl; and, substituted alkyl, alkenyl and cycloalkyl, for example, by halogen, a sulphonic acid derivative, such as SO3H, CF3, hydroxy, alkoxy, acyl, alkylamino, pyridyl. Cycloalkyl is preferably unsubstituted. Acyl includes C1-12, e.g. C1-6acyl, particularly C1-4acyl. Acyl includes unsubstituted acyl and substituted acyl, for example, by hydroxy, alkoxy, amino. Aryl includes phenyl. Aryl may be unsubstituted aryl or substituted aryl, for example by alkyl, alkoxy, acyl, halogen, hydroxy, unprotected or protected amino. Alkoxy includes alkoxy wherein the alkyl part is as defined above.
Heterocyclyl includes heterocyclyl having 5 or 6 ring members and 1 to 3 nitrogen, sulphur and/or oxygen hetero atoms including, for example, condensed heterocyclyl, such as for example benzthiazolyl. Heterocyclyl includes further unsubstituted hetercyclyl and substituted heterocyclyl, for example by oxo, alkoxy, hydroxy, thiono, mercapto, alkylthio, imino, alkylamino, alkylimino, amino, halogen, acyl, CF3, CHO, alkyl, cycloalkyl.
Carbamoyl includes the carbamoyl group or carbamoyl having alkyl and aryl residues.
Z1 denotes unsubstituted cycloalkyl, 1,4-cyclohexadienyl, heterocyclyl or aryl; and one or several fold substituted cycloalkyl, 1,4-cyclohexadiene, heterocyclyl or aryl; for example by carboxyl, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, xe2x80x94COxe2x80x94N(Z5Z6), xe2x80x94N(Z6)xe2x80x94COOZ, Z6COxe2x80x94, Z6OCOxe2x80x94, Z6COOxe2x80x94.
Z2 denotes hydrogen; CH2COOZ5; unsubstituted lower alkyl; one or several fold substituted lower alkyl, for example by carboxyl, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, xe2x80x94COZ5Z6, xe2x80x94N(Z6)xe2x80x94COOZ7, Z6COxe2x80x94, Z6OCOxe2x80x94 or Z6COOxe2x80x94.
Z3 denotes hydrogen or lower alkyl.
Z4 denotes hydrogen or an organic radical; preferably hydrogen; lower alkyl; cycloalkyl; aralkyl; acyl; carboxyalkyl; Z6COxe2x80x94, xe2x80x94C(Z7Z8)COOZ6 or, preferably in the case that Z1 in group 
denotes a group 2-amino-thiazol-4yl or 2-amino-thia-3,5-diazol-4yl,
Z4 denotes a group of formula 
xe2x80x83wherein
Z9 and Z10 independently of one another denote hydrogen or protected or unprotected carboxyl
Z11 denotes hydrogen or acetyl,
Z12 denotes unprotected or protected carboxyl,
Z13 denotes hydrogen or methyl,
Z14 denotes hydrogen; chloro; unprotected or protected carboxyl; methyl; isopropyl; hydroxy; methoxy; acetoxy,
Z15 and Z16 denote independently from one another hydrogen, hydroxy, methoxy, ethoxy, 2-methoxyethoxymethoxy, acetoxy, chloroacetoxy, butanoyloxy, methansulfonyloxy, p-toluenesulfonyloxy, amino, acetylamino, benzyloxycarbonylamino or methansulfonyl; or,
Z15 and Z16 denote together ethylendioxy or carbonyldioxy,
Z17 denotes hydrogen, hydroxy, acetoxy, methyl, methoxy, chloroacetoxy, with the proviso, that not all of Z14, Z15, Z16 and Z17 denote hydrogen,
Z18 and Z19 denote independently of one another hydrogen or methyl,
Z20, Z21, Z22, Z23 and Z24 denote independently of one another hydrogen, halogen or hydroxy,
Z25 and Z26 denote independently from one another hydrogen; C1-5alkyl; unsubstituted phenyl; or substituted phenyl,
Z27 denotes unsubstituted lower alkyl; or substituted lower alkyl,
Z28 and Z29 denote independently of one another hydrogen or hydroxy, and
n denotes 0 or 1,
Z5 denotes hydrogen, alkyl, preferably lower alkyl,
Z6 and Z7 independently of one another denote hydrogen or alkyl, preferably lower alkyl,
Z6 and Z7 together with the carbon atom denote cycloalkyl, and
Z5 and Z6 together denote cycloalkyl.
Z4 may be selected from the following groups: 
For example, Ac may denote a group of formula 
Preferably Ac denotes a compound of formula 
wherein
W denotes CH or N
V denotes CH or Nxe2x80x94O and
R3 denotes hydrogen, acyl, carboxyl, alkyl.
The configuration of R3 in group of xe2x80x94Cxe2x95x90Vxe2x80x94R3 may be syn [(Z)] and anti [(E)] and is preferably syn [(Z)].
If R3 denotes alkyl, R3 includes unsubstituted alkyl or substituted alkyl, for example by halogen, carboxyl. Preferably W denotes CH.
In another aspect the present invention provides a compound of formula 
wherein
W denotes CH or N
V denotes CH or Nxe2x80x94O
R1 denotes hydrogen or an ester moiety,
R2 denotes a group of formula 
xe2x80x83wherein
Y denotes hydrogen; unsubstituted lower alkyl; or substituted lower alkyl, by the residue of a carboxylic acid, a carboxylic acid ester or a carboxylic acid amide,
R4 denotes hydrogen, phenyl, cycloalkyl or lower alkyl
R5 denotes hydrogen, lower alkyl, heterocyclyl or a group of formulae 
xe2x80x83wherein
R7 denotes lower alkyl
R8 denotes hydrogen, cycloalkyl or lower alkyl
R9 denotes hydrogen or lower alkyl,
R10 denotes hydrogen, hydroxy; amino; phenyl; alkenyl; cycloalkyl; heterocyclyl; unsubstituted alkyl; substituted alkyl, by CF3, OH, alkoxy, carboxyl, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, pyridyl or a a sulfonic acid residue; a group of formula 
xe2x80x83wherein
R12 denotes hydrogen or lower alkyl,
Z denotes oxygen, sulphur, or Nxe2x80x94R13, wherein
R13 denotes hydrogen or lower alkyl, and
R11 denotes hydrogen; dihydroxyphenyl; cycloalkyl; heterocyclyl; unsubstituted lower alkyl; substituted lower alkyl by pyridyl or monoalkylamino, dialkylamino or trialkylamino; and,
R4 and R5 and/or R9 and R10 independently of one another together with the nitrogen denote heterocyclyl,
R6 denotes heterocyclyl, and
R3 denotes hydrogen; acyl; carboxyl; unsubstituted alkyl; substituted alkyl by halogen or carboxyl.
In another aspect the present invention provides a compound of formula 
wherein
R1p is the same as R1 in formula I,
Ac is as defined in formula I,
R2p denotes a group of formulae 
xe2x80x83wherein
Yp is the same as Y in formula IA,
R4p is the same as R4 in formula IA, and
R5p denotes hydrogen, cycloalkyl, lower alkyl or a group of formula 
xe2x80x83wherein
R8p is the same as R8 in formula IA,
Zp is the same as Z in formula IA,
R9p is the same as R9 in formula IA,
R7p denotes methyl,
R10p denotes hydrogen, lower alkyl or hydroxy, and
R4p and R5p and/or R9p and R10p independently of one another together with the nitrogen denote heterocyclyl, and
a compound of formulae IIbp, IIdp and IIep denote any tautomeric form, in free form, or, where such a form exists, in form of an acid addition salt, inner salt, quaternary salt or hydrate thereof.
In another aspect the present invention provides a compound of formula 
wherein
Ac is as defined in formula I
R1q is he same as R1 in formula IA, and
R2q denotes a group of formula 
xe2x80x83wherein
Yq is the same as Y in formula IA,
R4q is the same as R4 in formula IA, and
R5q denotes hydrogen, cycloalkyl, lower alkyl or a group of formulae 
xe2x80x83wherein
R7q is the same as R7 in formula IA,
R8q is the same as R8 in formula IA,
Zq is the same as Z in formula IA,
R9q is the same as R9 in formula IA,
R10q denotes hydrogen, lower alkyl or hydroxy, and
R4q and R5q and/or R9q and R10q independently of one another together with the nitrogen denote heterocyclyl, and
a compound of formulae IIbp, IIdp and IIep denote any tautomeric form, in free form, or, where such a form exists, in form of an acid addition salt, inner salt, quaternary salt or hydrate thereof.
In a further aspect the present invention provides a compound of formula 
wherein
R1s is the same as R1 in formula IA,
Vs is the same as V in formula IA,
Ws is the same as W in formula IA
R3s denotes hydrogen, lower acyl; unsubstituted alkyl; substituted lower alkyl, by carboxyl and/or fluoro; and
R2s denotes a group of formula 
xe2x80x83wherein
Ys denotes hydrogen; unsubstituted lower alkyl; or substituted alkyl by carboxyl,
R4s denotes hydrogen or lower alkyl, and
R5s denotes hydrogen; saturated or unsaturated, unsubstituted heterocyclyl having 5 or 6 ring members and 1 to 3 nitrogen hetero atoms; saturated or unsaturated one or several fold substituted heterocyclyl by oxo, lower alkyl, amino or CF3, having 5 or 6 ring members and 1 to 3 nitrogen hetero atoms; benzothiazolyl; or a group of formula 
xe2x80x83wherein
Zs is the same as Z in formula I,
R7s denotes lower alkyl,
R8s denotes hydrogen, cycloalkyl or lower alkyl,
R9s denotes hydrogen or lower alkyl,
R10s denotes hydrogen; phenyl; allyl; cycloalkyl; unsubstituted alkyl; substituted alkyl by CF3, dialkylamino, trialkylamino, hydroxy, pyridyl or SO3H, and
R11s denotes hydrogen; pyridyl; cycloalkyl; unsubstituted lower alkyl; substituted lower alkyl by pyridyl or trialkylamino; saturated or unsaturated heterocyclyl having 5 or 6 ring members and 1 to 3 nitrogen hetero atoms; or one or several fold substituted heterocyclyl by lower alkyl and/or thiono, having 5 or 6 ring members and 1 to 3 nitrogen hetero atoms;
R4s and R5s together with the nitrogen atom denote heterocyclyl selected from saturated, unsubstituted heterocyclyl having 5 or 6 ring members and 1 or 2 nitrogen hetero atoms; saturated, one or several fold substituted heterocyclyl by oxo or lower alkyl, having 5 or 6 ring members and 1 or 2 nitrogen hetero atoms; and/or
R9s and R10s together with the nitrogen atom denote saturated, unsubstituted heterocyclyl having 5 or 6 ring members and 1 or 2 nitrogen and/or oxygen hetero atoms; unsaturated, one or several fold substituted heterocyclyl by CHO or lower alkyl, having 5 or 6 ring members and 1 or 2 nitrogen and/or oxygen hetero atoms.
In another aspect the present invention provides a compound of formula 
wherein
W denotes CH or N
V denotes CH or Nxe2x80x94O
R1 denotes hydrogen or an ester moiety, and
R2 denotes a group of formula
xe2x80x94N(R4R5)xe2x80x83xe2x80x83IIb
xe2x80x83wherein
R4 is as defined in claim 1 and
R5 denotes a group of formula 
xe2x80x83wherein
Z denotes xe2x80x94Nxe2x80x94R13, wherein
R13 is as defined in claim 1, and
R9 and R10 together with the nitrogen atom denote heterocyclyl which is a piperazinyl.
In another aspect the present invention provides a compound selected from
7-[[(2-amino-4-thiazolyl)-(Z)-(hydroxyimino)acetyl]amino]-3-[[(aminoininomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid (compound of Example 2),
7-[[(2-amino-4-thiazolyl)-(Z)-(hydroxyimino)acetyl]-amino]-3-[[(piperazinoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid (compound of Example 96)
7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluormethoxyimino)acetyl]amino]-3-[[(piperazinoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid (compound of Example 139).
A compound of formulae I, IA, Ip, Iq, Is, IVi, IVa and VIa may exist in equilibrium with tautomeric forms. The present invention includes a compound of formulae I, IA, Ip, Iq, Is IVi, IVa and VIa in any tautomeric form in which it may exists.
In another aspect the present invention provides a process for the production of a compound of formula I by reaction of a compound of formula 
wherein Ac is as defined in formula I and
a) either
xcex1) Rb denotes hydroxy and Rc and Rd together form a bond, or
xcex2) Rd denotes hydrogen, a cation, an ester forming group or a silyl group, and Rb and Rc together denote oxo, in free form or in form of an acid addition salt with a group of formula
H2Nxe2x80x94R2xe2x80x83xe2x80x83IV
xe2x80x83wherein R2 is as defined in formula I, or
b) reacting a compound of formula 
xe2x80x83wherein R1 and R2 are as defined in formula I, with a compound of formula
Ac-Xxe2x80x2xe2x80x83xe2x80x83VII
xe2x80x83wherein Ac is as defined in formula I and Xxe2x80x2 denotes a leaving group.
If desired reactive groups may be protected with protecting groups, which may be, or, which are split off under the reaction conditions, or after termination of the reaction described above. A compound of formula I wherein R1 denotes hydrogen may be converted into a compound of formula I, wherein R1 denotes an carboxylic acid ester group. A compound of formula I may be isolated from the reaction mixture in conventional manner.
Process a) may be carried out as follows:
A compound of formula III in a solvent which is inert under the reaction conditions, such as water, a mixture of water and a lower alcohol and/or dioxane, or a dipolar aprotic solvent, for example dimethylformamide or dimethylsulfoxide, optionally mixed with an alcohol or water is reacted with a compound of formula IV at a temperature of about xe2x88x9220 to 50xc2x0 C. An optimal pH may be adjusted by addition of an inorganic or organic acid or base. A compound of formula I thus obtained may be isolated in conventional manner, for example by addition of an anti-solvent or by chromatographic techniques.
Process b) may be carried out as follows:
The reaction may be carried out as conventional, e.g. a compound of formula VI may be reacted with a compound of formula VII in a solvent, for example dissolved or suspended in a mixture of acetone/water, for example at room temperature.
A reactive group may be protected, preferably by silyl protecting group technology. Suitable solvents include solvents which are inert under the reaction conditions, such as chlorinated hydrocarbons, nitrites, such as acetonitrile, ethers, such as tetrahydrofuran or a mixture of such solvents. Further suitable solvents include dipolar aprotic solvents, e.g. N,N-dimethylformamide. Protecting groups may be split off in conventional manner.
A starting compound of formula II may, for example, be obtained by
a) reaction of a compound of formula 
xe2x80x83wherein either
xcex1) Ra denotes a salt of xe2x80x94NH2 with an inorganic or organic acid, Rxe2x80x2b denotes hydroxy, and Rxe2x80x2c and Rxe2x80x2d denote together a bond, or
xcex2) Ra denotes NH2, Rxe2x80x2d denotes hydrogen and Rxe2x80x2b and Rxe2x80x2c together denote oxo, with a silylation agent and, a compound obtained in step a) of formula 
xe2x80x83wherein Sil denotes a silyl group and either
xcex1) Rxe2x80x3b denotes xe2x80x94OSil and Rxe2x80x3c and Rxe2x80x3d together denote a bond
xcex2) Rxe2x80x3c denotes Sil and Rxe2x80x3b and Rxe2x80x3c together denote oxo is acylated either directly in the reaction mixture or after isolation from the reaction mixture.
Acylation may be carried out in conventional manner.
A compound of formula IIc may be obtained
a) for the production of a compound of formula 
xe2x80x83which is an the form of a salt of an inorganic or organic acid and wherein Rxe2x80x2xe2x80x3b denotes hydroxy and Rxe2x80x2xe2x80x3c and Rxe2x80x2xe2x80x3d together denote a bond, reacting a salt of an inorganic or organic acid of a compound of formula 
xe2x80x83wherein
R14 and R15 are the same or different and each denote hydrogen or an organic residue in an organic solvent optionally in the presence of water with ozone
b) for the production of a compound of formula 
xe2x80x83treating a compound of formula IIIe wherein Rxe2x80x2xe2x80x3b, Rxe2x80x2xe2x80x3c and Rxe2x80x2xe2x80x3d ar as defined above, with a base.
Compounds of formulae IV are partially new and may be obtained analogously to conventional methods, or, as described in the examples.
In another aspect the present invention provides a compound of formula
H2Nxe2x80x94R2ixe2x80x83xe2x80x83IVi
wherein
R2i denotes a group of formula
xe2x80x94N(R4iR5i)xe2x80x83xe2x80x83IIbi
xe2x80x83wherein
R4i is the same as R4 in formula I and denotes preferably hydrogen or alkyl and
R5i denotes a group of formula 
xe2x80x83wherein
Zi denotes Nxe2x80x94R13i, wherein
R13i is the same as R13 in formula I and denotes preferably hydrogen or alkyl, and
R9i and R10i together with the nitrogen atom denote heterocyclyl which is a piperazinyl; or
R4i is the same as R4 in formula I and denotes preferably hydrogen, and
R5i denotes a group of formula 
xe2x80x83wherein
R8i denotes alkyl, preferably at least C2 alkyl; or cycloalkyl, preferably cyclopropyl, and
R7i denotes alkyl, preferably methyl; or
R4i is the same as R4 in formula I and denotes preferably hydrogen or alkyl and
R5i denotes a group of formula 
xe2x80x83wherein
Zi denotes Nxe2x80x94R13i, wherein
R13i denotes hydrogen, alkyl or cycloalkyl, preferably hydrogen or alkyl
R9i denotes hydrogen and
R10i denotes CH2CF3, C(CH3)3, OH or an alkyl group having at least 2 carbon atoms which is substituted by dialkyl amine or trialkyl ammonium, hydroxy; or
R4i is the same as R4 in formula I and denotes preferably hydrogen
R5i denotes a group of formula 
xe2x80x83wherein
Zi denotes Nxe2x80x94R13i, wherein
R13i denotes alkyl or cycloalkyl, preferably alkyl, and
R9i and R10i together with the nitrogen atom denote heterocyclyl which is morpholyl or pyrrolidinyl; or
R4i is the same as R4 in formula I and denotes preferably hydrogen
R5i denotes a group of formula 
xe2x80x83wherein
Zi denotes Nxe2x80x94R13i, wherein
R13i denotes hydrogen, alkyl or cycloalkyl, preferably hydrogen, and
R9i denotes hydrogen, and
R10i denotes cycloalkyl, preferably cyclopropyl; or
R4i is the same as R4 in formula I and denotes preferably hydrogen
R5i denotes a group of formula 
xe2x80x83wherein
Zi denotes Nxe2x80x94R13i, wherein
R13i is the same as R13 in formula I and denotes preferably hydrogen,
R9i denotes hydrogen or alkyl, preferably hydrogen, and
R10i denotes a group
xe2x80x94Nxe2x95x90CH-Phe
xe2x80x83wherein Phe denotes phenyl, preferably a dihydroxy phenyl, or
R4i is the same as R4 in formula I and denotes preferably hydrogen
R5i denotes a group of formula 
xe2x80x83wherein
Zi denotes Nxe2x80x94R13i, wherein
R13i denotes hydrogen, alkyl or cycloalkyl, preferably hydrogen,
R11i denotes a dihydroxyphenyl or substituted pyrrolidyl by alkyl; or
Zi denotes oxygen and
R11i denotes the group of formula 
In another aspect the present invention provides a compound of formula 
wherein
Rx is a group of formula 
Ry is NH and
Rz is hydrogen; or
Rx is a group of formula 
Ry is NH and
Rz is CH3; or
Rx is xe2x80x94SCH3 
Ry is a group of formula 
xe2x80x83and
Rz is hydrogen, or
Rx is a group of formula 
Ry is Nxe2x80x94CH3 and
Rz is hydrogen; or
Rx is the group 
Ry is Nxe2x80x94C2H5 and
Rz is hydrogen; or
Rx is the group 
Ry is oxygen and
Rz is hydrogen.
Compounds of formulae VI are partially new and may be obtained analogously to conventional methods, or, as described in the examples.
In another aspect the present invention provides a compound of formula 
wherein
R1 is as defined in formula I and
Rxx denotes the group 
xe2x80x83wherein
Rx, Ry and Rz as defined above.
In this specification unless otherwise indicated terms such as xe2x80x9ccompound of formula I, IA, Is, Ip, Iq, IVi, IVa and VIaxe2x80x9d embrace the compound in any form, for example in salt form and free base form. The present invention thus includes a compound in free or base form or, where such forms exist, in salt form, for example in form of an acid addition salt, inner salt, quaternary salt and/or in solvate, for example hydrate form thereof. A salt may be a pharmaceutically acceptable salt of a compound of formulae I, IA, Is, Ip, Iq such as a metal salt or an amine salt. Metal salts include for example sodium, potassium, calcium, barium, zinc, aluminum salts, preferably sodium or potassium salts. Amine salts include for example trialkylamine, procaine, dibenzylamine and benzylamine salts. A free form of a compound of formulae I, IA, Is, Ip, Iq, IVi, IVa and VIa may be converted into a salt form and vice versa.
In a further aspect the present invention provides a compound of formulae I, IA, Is, Ip, Iq, IVi, IVa and VIa in free form; or in salt form, for example in acid addition salt form or in metal salt form; and a compound of formulae I, IA, Is, Ip, Iq, IVi and VIa and VIa in solvate form.
A compound of formula I may also be obtained analogously to other processes conventional in the xcex2-lactam chemistry.
The compounds of formula I, hereinafter designated as xe2x80x9cactive compound(s) of the inventionxe2x80x9d exhibits pharmacological activity and are therefore useful as pharmaceuticals. In particular, the active compounds of the invention show antimicrobial, e.g. antibacterial, activity against gram negative and gram positive bacteria such as Pseudomonas, e.g. Pseudomonas aeruginosa, Pseudomonas fluorescens; Enterobacter, e.g. Enterobacter cloacae; Enterococcus, e.g. Enterococcus faecalis; Moraxella, e.g. Moraxella catarrhalis; Haemophilus, e.g. Haemophilus influenza; Klebsiella, e.g. Klebsiella edwardsii, Klebsiella pneumoniae; Streptococcus, e.g. Streptococcus pneumoniae, Streptococcus durans, Streptococcus faecium, Streptococcus pyogenes; Staphylococcus, e.g. Staphylococcus aureus, Staphylococcus pyogenes; Escherichia, e.g. Escherichia coli; and Proteus, e.g. Proteus mirabilis in vitro in the Agar Dilution Test according to National Commitee for Clinical Laboratory Standards (NCCLS) 1993, Document M7-A3Vol.13, No. 25: xe2x80x9cMethods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobicallyxe2x80x94Third Edition, Approved Standardxe2x80x9d and in vivo in the septikaemic mouse model. The active compounds of the invention show activity in the mouse when administerd at dosages from about 0.05 to 50 mg/kg body weight (ED50 values).The active compounds show an MHK(xcexcg/ml) in the Agar Dilution Test from about 0.005 to ca. 50. The active compounds of the invention show an surprising overall activity spectrum.
It has, for example, been determined that the MHK (xcexcg/ml) of the compound of Example 139 against, for example Enterococcus faecalis strains ATTC 29212 or ATCC 51299, is of ca. 0.08 to 0.25; ainst Staphylococcus aureus strains ATCC 29213 or ATCC 9144 is of ca. 0.2 to 0.4 and against Pseudomonas aeruginosa strain 27853 is ca. 0.8.
The active compounds of the invention are, therefore, useful for the treatment of microbial, e.g. bacterial diseases.
In another aspect the present invention provides a compound of claim 1 for use as a pharmaceutical, preferably as an antimicrobial agent, such as an antibiotic.
In a further aspect the present invention provides a compound of claim 1 for use in the preparation of a medicament for the treatment of microbial diseases, for example of diseases caused by bacterias selected from Pseudomonas, Enterobacter, Enterococcus, Moraxelia, Haemophilus, Klebsiella, Streptococcus, Staphylococcus, Escherichia, and Proteus.
In a further aspect the present invention provides a method of treatment of microbial diseases which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.
For this indication, the appropriate dosage will, of course, vary depending upon, for example, the compound of formula I employed, the host, the mode of administration and the nature and severity of the conditions being treated. However, in general, for satisfactory results in larger mammals, for example humans, an indicated daily dosage is in the range from about 0.05 to 5 g, for example 0.1 to about 2.5 g, of an active compound of the invention conveniently administered, for example, in divided doses up to four times a day.
An active compound of the invention may be administered by any conventional route, for example orally, e.g. in form of tablets or capsules, or parenterally in the form of injectable solutions or suspensions, e.g. in analogous manner to cefotaxime.
The compound 7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluormethoxyimino)acetyl]amino]-3-[[(piperazinoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid (compound of Example 139) is the preferred compound of the invention for use as an antimicrobial agent.
It has, for example been determined that the MHK (xcexcg/ml) of the compound of Example 139 (tested in form of the trihydrochloride) against, for example Streptococcus pneumoniae, strain ATCC 49619 is ca. 0.01 whereas, for example ceftriaxone shows an MHK (xcexcg/ml) of ca. 0.02. It is therefore, indicated that for the treatment of microbial diseases, e.g. bacterial diseases the preferred compounds of the invention may be administered to larger mammals, for example humans, by similar modes of administration at similar dosages than conventionally employed with ceftriaxone.
The compounds of formula I may be administered in pharmaceutically acceptable salt form, e.g. acid addition salt form or base addition salt form or in the corresponding free forms, optionally in solvate form. Such salts exhibit the same order of activity as the free forms.
The present invention also provides pharmaceutical compositions comprising a compound of formula I in pharmaceutically acceptable salt form or free form in association with at least one pharmaceutical carrier or diluent.
Such compositions may be manufactured in conventional manner.
Unit dosage form may contain, for example 10 mg to about 1 g, for example 10 mg to about 700 mg.
In the following Examples the temperatures indicated are in degree Celsius.